Adverse event rates low, but only a minority reached uric acid target

Action Points

A treat-to-target strategy with allopurinol among patients with gout was associated with a low incidence of adverse events, but only a minority of patients actually reached the target serum uric acid level below 6 mg/dL.

Note that a total of 55.1% of patients experienced any adverse event, with the most common being upper respiratory tract infection, diarrhea, and arthralgia.

A treat-to-target strategy with allopurinol among patients with gout was associated with a low incidence of adverse events, but only a minority of patients actually reached the target serum uric acid level below 6 mg/dL, a large international study found.

Among 1,732 patients with gout, 10.7% experienced a treatment-emergent adverse event possibly related to allopurinol during 6 months of treatment, and serious adverse events -- all considered unrelated to treatment -- occurred in 2.9%, according to Michael A. Becker, MD, of the University of Chicago, and colleagues.

Allopurinol has been used in the treatment of gout for nearly 50 years, and is the most common first-line serum urate-lowering drug, typically initiated in doses below 100 mg/day to minimize the risk of the potentially lethal allopurinol hypersensitivity syndrome.

Subsequent titration usually includes dose increases of 100 mg at 2 to 4 week intervals, guided by monitoring of uric acid levels. In the U.S., allopurinol is approved in doses up to 800 mg/day, but doses above 300 mg/day are not commonly used.

Despite the drug's long history of use, few safety data are available for higher doses. Becker and colleagues enrolled patients from 169 centers in LASSO (long-term safety study evaluating outcomes in gout patients), which was an open-label study of patients who had experienced at least two gout flares in the previous year.

The study investigators were allowed to determine dosage adjustments individually but were encouraged to titrate up as needed to reach the target uric acid level.

For the purpose of analysis at study completion, patients were divided into maximum dosage categories of less than 300 mg/day, 300 mg/day, and more than 300 mg/day.

The majority of patients were white males. Mean duration of gout was 10 years, participants' average age was 51, and mean body mass index was 34.4 kg/m2. More than half had hypertension and more than one-third had dyslipidemia.

Mean baseline serum uric acid level was 8.8 mg/dL and was higher than 6 mg/dL in 96% of participants.

The maximum daily dose of allopurinol was less than 300 mg in 14.4% of patients, 300 mg in 65.4%, and above 300 mg in 20.2%.

Almost all patients also were taking prophylaxis for gout flares, usually with colchicine, although a minority were given nonsteroidal anti-inflammatory drugs (NSAIDs) for this purpose.

A total of 55.1% of patients experienced any adverse event, with the most common being upper respiratory tract infection, diarrhea, and arthralgia. Serious adverse events included pneumonia, acute myocardial infarction, and cellulitis.

There were no cases of allopurinol hypersensitivity syndrome.

Among patients receiving less than 300 mg/day, 10.8% discontinued treatment because of adverse events, as did 3.6% of those on 300 mg/day and 1.7% of those taking more than 300 mg/day. These adverse events included diarrhea, rash, and liver enzyme elevations.

A possible explanation for the observation that more patients in the low-dose group discontinued for adverse events was that early toxicity could have precluded up-titration, the authors suggested.

The rate of major adverse cardiovascular events was 1.42/100 patient-years, which was similar to what has been seen in previous studies of patients with gout, "a population recognized to be at elevated cardiovascular risk," the authors noted.

More patients in the high-dose group met the uric acid target at 6 months (48.3%) than in the 300-mg group (35%) or the low-dose group (22.4%).

One-third of patients experienced a gout flare, with the highest incidence being in the high-dose group (44.3%) compared with the 300-mg group (33.7%) or the low-dose group (16.4%). Most of the flares occurred within the first month.

Baseline characteristics associated with flare included higher uric acid levels, higher creatinine clearance rate, non-use of allopurinol prior to study entry, and use of NSAIDs rather than colchicine for prophylaxis.

The investigators concluded that allopurinol was "generally well tolerated" during the study, seeing no new safety signals even at doses above 300 mg/day.

"However, despite encouragement to treat to target, 300 mg was the most commonly used dose and significant proportions of patients did not achieve target serum uric acid levels," they observed.

Limitations of the study included its open-label design and the permitted use of medications other than allopurinol.

The study was funded by Ardea Biosciences.

Becker and co-authors disclosed no relevant relationships with industry.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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